Despite the development of numerous drugs and therapeutic agents for treating diseases, problems involving the passage of biological barriers (e.g., skin, oral mucosa, and brain-blood barrier) and the efficiency of drug delivery still remain to be improved in view of delivering the drugs into the body.
Generally, drugs are orally administered in a dosage form of a tablet or capsule, but numerous drugs can be effectively delivered through only the above administration manner since they are digested or absorbed in the gastrointestinal tract or lost due to hepatic mechanisms. Moreover, some drugs cannot be efficiently diffused when passed through the intestinal mucosa. Also, patient compliance is problematic (e.g., patients who need take drugs at predetermined intervals or cannot take drugs).
Another general technique for drug delivery is to use conventional needles. While this technique is more effective than oral administration, it causes pain at the injection sites, local damage to the skin, bleeding, or infections at the injection sites.
In order to solve the above problems, several microstructures including microneedles have been developed. Recently developed microneedles have been used for in vivo delivery of drugs, blood collecting, detection of in vivo analytes, and the like.
The microneedles are characterized by painless skin penetration and causing no wounds unlike existing needles, and the diameter at the top for the minimum sharpness is important in the painless skin penetration. In addition, the microneedle is required to have a sufficient physical hardness since it needs to pass through the stratum corneum of 10-20 μm, which is the thickest barrier in the skin. The microneedle needs to also have an appropriate length in order to improve the efficiency of drug delivery by arriving in capillary vessels.
As for the method using a mold (1) among existing microneedle manufacturing methods, a microneedle was manufactured by filling a biodegradable solution in a microneedle-shaped mold and then hardening and separating the mold (Jung-Hwan Park et al., Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery, Journal of Controlled Release 104:51-66(2005)).
In addition, as for the microneedle manufacturing method through contact and stretching of an existing viscous solution, a microneedle was molded by contacting the viscous solution with a pillar structure or a substrate, followed by stretching (Kwang Lee and Hyungil Jung, Drawing lithography for microneedles: A review of fundamentals and biomedical applications, Biomaterials 33:7309-7326(2012)). This manufacturing method includes a procedure of binding the viscous solution to a supporter through the contact and then performing stretching, and a procedure of performing solidification in a microneedle shape and then cutting the weakest portion between the microneedle and the pillar structure or substrate through physical destruction.
The existing microneedle manufacturing methods as described above are characterized in that the microneedle is molded through contact with a solution. The existing microneedle manufacturing methods have limitations, such as the loss during the separation procedure after the contact or the restriction of surface characteristics that can be manufactured, due to making the contact.
Besides, the existing methods for manufacturing a microstructure such as a microneedle include a method using air blowing, which is disclosed in WO 2010-039006, and a method using three-dimensional downward flow, which is disclosed in WO 2009-154411.
Skin is composed of stratum corneum (<20 μm), epidermis (<100 μm), and dermis (300 to 2,500 μm), on the outer layer thereof. Therefore, in order to deliver drugs and skin care ingredients to a specific layer of the skin without pain, the microneedle needs to be manufactured to have a top diameter of within 30 μm, an effective length of 200 to 2,000 μm, and a sufficient hardness to penetrate the skin, which is also effective in delivering the drugs and skin care ingredients. In addition, in order to deliver drugs or skin care ingredients through a biodegradable solid microneedle, process steps that may destroy activities of the drugs and skin care ingredients, such as high-heat treatment, treatment with an organic solvent, and the like, need to be excluded from the microneedle manufacturing process. However, there are no conventional techniques sufficiently satisfying these requirements.
Therefore, novel methods for manufacturing microstructures capable of solving the above-mentioned problems have been continuously required.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosures of cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and details of the present invention are explained more clearly.